The steroids are a well known and large family of molecules, characterized by a tetracyclic, cyclopenta[.alpha.]phenanthrene structure. The family includes hormones, some vitamins, and a number of drugs. Examples of the latter include cortisone and corticosterone.
It is impossible to state a general rule for how therapeutically active steroids function, but they are usually considered to be anti-inflammatory agents--i.e., they interact with receptors in target cells, thereby initiating or interfering with pathways leading to production of molecules involved in an immune response (cytokines, antibodies, stimulatory factors, etc.).
Allergic diseases are among those most commonly treated via administration of steroids, and to a certain extent these drugs are successful. Steroids frequently elicit unwanted side effects, however. In addition, there are subpopulations of subjects who are resistant to treatment with steroids. A comprehensive explanation for why these subpopulations are resistant to steroid treatment and therapy is not known.
The class of molecules referred to collectively as cytokines has become recognized as a potential source of therapeutic agents. One subclass of cytokines are the interferons and interferon derivatives, one of which, gamma interferon or "immune interferon" is the subject of this invention.
Gamma interferon is recognized as a useful therapeutic agent for a number of conditions. U.S. Pat. No. 4,944,94, to Ammann, the disclosure of which is incorporated by reference, teaches that gamma interferon alone or in combination with corticosteroids, can be used to induce individuals afflicted with respiratory disease syndrome (RDS), or idiopathic RDS to produce additional surfactants in the lungs. In a similar manner, PCT application W087/07842, postulates a role for gamma interferon in the treatment of malignant diseases, rheumatic diseases, and allergic diseases. The gamma interferon is used in combination with anti-inflammatory or anti-pyretic agents in the treatment of these diseases and conditions. Additional evidence for a therapeutic role for gamma interferon may be found in Ezekowitz et al., New Eng. J. Med. 319: 146-151 (July, 1988), which teaches the use of subcutaneously administered gamma interferon as a therapy for X-linked chronic granulomatous disease. This study was followed up on in New Eng. J. Med. 324(8): 509-516 (February, 1991), which presents the results of a controlled trial studying the role of gamma interferon in the prevention of infection in chronic granulomatous.
Independent of work on gamma interferon, additional studies have been carried out to study the role of the family of cytokines known as interleukins on the immune system. The mechanism of action by which the class of immunoglobulin known as IgE has been of particular interest, because these immunoglobulins are involved in the allergic response. IgE binds to receptors on the surface of mast cells and basophils, leading to production and release of various molecules. Romagnani, Immunol. Today 11(9): 316-321 (1990), discussed the role of interleukin 4 ("IL-4") on IgE synthesis. The paper discusses how IL-4 and gamma interferon have opposite regulatory effects on IgE production--the former induces synthesis of the IgE, while the latter inhibits it. Vercelli et al., J. Allerg. & Clin. Immunol 88(3): 285-297 (1991), discuss how IL-4 mediates "class switching", i.e., switching of production by B cells from one type of immunoglobulin, such as IgM, to IgE. Boguniewicz et al., Am. J. Med. 88: 365-370 (April 1990), the disclosure of which is incorporated by reference, observed elevated IgE levels in the condition known as atopic dermatitis. Given the role of gamma interferon in inhibiting the effect of IL-4 on IgE stimulation, tests were carried out in which gamma interferon was administered in vivo to patients with atopic dermatitis. At all doses tested, the interferon was linked to a lessening in clinical severity of the disease. These studies are discussed, again, by Jujo et al., Leung et al., and Schneider et al., all at J. All. Clin. Immunol. 87: 383 (1991), all of which are incorporated by reference, which showed (i) that patients with atopic dermatitis had increased IL-4 levels and decreased gamma interferon levels (Jujo); (ii) that one could normalize IL-4 induced proliferative responses by administering gamma interferon (Leung), and (iii) that clinical severity of atopic dermatitis could be reduced by administering the interferon (Schneider). Reinhold et al., Lancet, May 26, 1990, page 1282 confirmed this.
In PCT Application W091/07984 to Leung, the disclosure of which is incorporated by reference, the results discussed supra are summarized in a patent application directed to the treatment of atopic dermatitis and steroid-dependent asthma. "Steroid-dependent asthma" is a condition in which patients afflicted with asthma must take steroid drugs, generally systemically, in order to alleviate the parameters involved with asthma.
Asthma is characterized by several "markers" including increased levels of serum IgE and eosinophils--markers identical to those observed in atopic dermatitis. When the observation set forth in the PCT application was tested in clinical trials involving subcutaneous administration of gamma interferon, however, the results did not show significant clinical improvement in patients with steroid dependent asthma. See, Boguniewicz et al., American Academy of Allergy and Immunology (Abstract, 1992--in press).
The form of asthma known as steroid resistant asthma is caused by unknown mechanisms. It is characterized, however, by persistent T cell activation.
In view of the teachings in the art that gamma interferon is of potential efficacy in treating steroid dependent asthma, it is surprising to find that it is effective against steroid resistant conditions such as steroid resistant asthma. This is the subject of the invention described herein, as elaborated upon in the disclosure which follows.